Benfica and Valencia secured convincing away wins to take a giant step toward the Europa League quarterfinals on Thursday while Real Betis surprisingly beat Sevilla 2-0 in a fierce Spanish derby played for the first time on the European stage.
Brazilian defender Luisao scored two second-half goals to help Benfica beat Tottenham 3-1 and cap a good night for Portugal's top clubs in the last-16 first legs, with Porto defeating Napoli 1-0 at home.
Valencia defied the early sending-off of Seydou Keita to beat Ludogorets Razgrad 3-0 away and Lyon was the night's other big winner, coming from behind to thrash Viktoria Plzen 4-1.
Germany striker Mario Gomez grabbed a late equalizer for Fiorentina in a 1-1 draw at Juventus in an all-Italian matchup while AZ Alkmaar beat Anzhi Makhachkala 1-0 and Basel drew 0-0 with Red Bull Salzburg, which failed to win in Europe's second-tier competition for the first time this season.
The second legs will be played next week.
At the end of a week when Arsenal and Manchester City exited the Champions League, English woes in Europe continued as Tottenham was outplayed at White Hart Lane by Benfica, last season's beaten finalist.
Spurs manager Tim Sherwood was seeking a response from his players after attacking their character and desire following Saturday's 4-0 loss to Chelsea in the Premier League but more poor defending cost them dear.
After Rodrigo opened the scoring for Benfica with a low curling shot in the 29th, Luisao doubled the lead in the 58th when he lost his marker at a corner and powered home a header.
Christian Eriksen pulled a goal back for Spurs with a superb free kick but Luisao slammed a close-range finish in off the bar after another set piece with six minutes to go, leaving Benfica in a commanding position.
Sherwood squared up to counterpart Jorge Jesus after the visitors' third goal after the Benfica coach held up three fingers in a goading celebration. They didn't shake hands after the match.
''I thought his team were very good, got a lot of class,'' Sherwood said. ''It's a pity he doesn't.''
Betis will also take a two-goal lead into a home second leg after strikes by Leo Baptistao and Salva Sevilla settled its 108th derby match against Sevilla, which started the game as the favorite.
Betis, bottom of the Spanish league, was coming off consecutive losses at Sevilla by a combined 9-1 score going into the match.
Valencia virtually sealed its place in the last eight despite playing most of its game in Bulgaria with 10 men following the 24th-minute red card to Keita, who brought down Roman Bezjak in the penalty box.
Bezjak's spot kick was saved and the Spanish visitors added goals by Fede Cartabia and Philippe Senderos to the opener scored by Antonio Barragan in the fifth minute. Juninho Quixada was sent off with 10 minutes to go for Ludogorets, which eliminated Lazio in the last 32.
Lyon, the only French side left in the competition, went behind after two minutes but surged back thanks to a double from Gueida Fofana and other goals by Alexandre Lacazette and Arnold Mvuemba.
Jackson Martinez scored Porto's goal in a 1-0 win over Napoli, which is coached by the man who led Chelsea to last season's Europa League title - Rafael Benitez.
Juventus beat Fiorentina 1-0 in Serie A on Sunday to tighten its grip atop the standings and went ahead four days later through Arturo Vidal in the third minute. However, Gomez, the former Bayern Munich striker, controlled a pass from Josip Ilicic and smashed a shot through goalkeeper Gianluigi Buffon's legs to grab a draw for the visitors.
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