Robin Lopez had 15 points for the Hornets, who played without leading scorer Ryan Anderson because of the flu.
Anthony Davis added 18 points and 14 rebounds, Ryan Anderson had 14 points, and Greivis Vasquez had 11 points and 11 assists.
Ryan Anderson scored 14, while Lopez had 13 points and 11 rebounds.
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The Hornets cut it to three three times inside the final half-minute, with Ryan Anderson, who scored 13 points, hitting a 3 and a tough turnaround, and Vasquez adding a 3.
Stuart Broad, Ryan Sidebottom and James Anderson all kept their heads at the end, producing yorker after yorker to send the holders home.
United also replaced Rooney with Carlos Tevez and Anderson with Ryan Giggs in what was clearly a last throw of the dice by Ferguson as time ran out.
He has been instrumental in helping seamers Ryan Sidebottom, James Anderson and Stuart Broad produce a string of consistent performances in the 3-2 series win in Sri Lanka.
Jaffer took a boundary off Ryan Sidebottom, Karthik crashed Anderson to the point fence again and India looked well on the way to a 10-wicket victory.
Having begun in a hurry with the key wickets of Hashim Amla (75) and Jacques Kallis (7) - brilliant catches by Matt Prior and James Anderson rewarding Stuart Broad and Ryan Sidebottom respectively - England had fewer answers to De Villiers and Boucher.
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Although Ryan Sidebottom was unable to find his best rhythm, Anderson was immediately in tune, pitching the ball on a full length and finding reward with prodigious movement.
But their bogey side United leveled in the 25th minute through veteran Ryan Giggs' superb free-kick, then fellow midfielder Anderson made it 2-1 four minutes before halftime with his first goal in open play for the club.
First, he pulled Ryan Sidebottom for a majestic maximum before using effortless timing to send Anderson over the ropes at square leg.
In the bowling department, Ryan Sidebottom and Stuart Broad have fully justified their selections ahead of James Anderson, while all-rounder Tim Bresnan has chipped in with crucial wickets and runs.
Anderson's best save probably was a stick stop on Ryan Carter late in the second period after a Senators turnover during a power play set up a 2-on-1, short-handed chance.
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United made a double substitution with 25 minutes left, sending on Ryan Giggs - making his 800th appearance for the club - and Berbatov for Anderson and Tevez.
South Africa's batsmen were put on the back foot early on by some good England bowling - Graeme Smith needing 13 balls to score his first run as Ryan Sidebottom started the match with a maiden, having been recalled for the rested James Anderson.
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